Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Climate change and plankton phenology in freshwater: current trends and future commitments

A solid body of empirical, experimental and theoretical evidence accumulated over recent years indicated that freshwater plankton experienced advance in phenology in response to climate change. Despite rapidly growing evidence for phenological changes, we still lack a comprehensive understanding of how climate change alters plankton phenology in freshwater. To overcome current limitations, we need to shed some light on trends and constraints in current research. The goal of this study is to identify current trends and gaps based on analysis of selected papers, by the help of which we can facilitate further advance in the field. We searched the literature for plankton phenology and confined our search to studies where climate change has been proposed to alter plankton phenology and rates of changes were quantified. We did not restrict our search for empirical ontributions; experimental and theoretical studies were considered as well. In the following we discuss the spatio-temporal setting of selected studies, contributions of different taxonomic groups, emerging methodological constraints, measures of phenological trends; and finally give a list of recommendations on how to improve our understanding in the field. The majority of studies were confined to deep lakes with a skewed geographical distribution toward Central Europe, where scientists have long been engaged in limnology. Despite these findings, recent studies suggest that plankton in running waters may experience change in phenology with similar magnitude. Average rate of advancement in phenology of freshwater plankton exceeded those of the marine plankton and the global average. Increasing study duration was not coupled either with increasing contribution of discontinuous data or with increasing rates of phenological changes. Future studies may benefit from i) delivering longterm data across scientific and political boundaries; ii) extending study sites to broader geographical areas with a more explicit consideration of running waters; iii) applying plankton functional groups; iv) increasing the application of satellite data to quantify phytoplankton bloom phenology; v) extending analyses of time series beyond the spring period; vi) using various metrics to quantify variation in phenology; vii) combining empirical, experimental and theoretical approaches; and last but not least viii) paying more attention to emergence dynamics, nonresponding species and trophic mismatch.

Mitochondrial DNA, segments I and II, its applications in population genetics and forensic sciences

The investigations of human mitochondrial DNA (mtDNA) have considerably contributed to human evolution and migration. The Middle East is considered to be an essential geographic area for human migrations out of Africa since it is located at the crossroads of Africa, and the rest of the world. United Arab Emirates (UAE) population inhabits the eastern part of Arabian Peninsula and was investigated in this study. Published data of 18 populations were included in the statistical analysis. The diversity indices showed (1) high genetic distance among African populations and (2) high genetic distance between African populations and non-African populations. Asian populations clustered together in the NJ tree between the African and European populations. MtDNA haplotypes database of the UAE population was generated. By incorporating UAE mtDNA dataset into the existing worldwide mtDNA database, UAE Forensic Laboratories will be able to analyze future mtDNA evidence in a more significant and consistent manner. ^

An assessment of natural and human disturbance effects on Mexican ecosystems: current trends and research gaps

Mexico harbors more than 10% of the planet’s endemic species. However, the integrity and biodiversity of many ecosystems is experiencing rapid transformation under the influence of a wide array of human and natural disturbances. In order to disentangle the effects of human and natural disturbance regimes at different spatial and temporal scales, we selected six terrestrial (temperate montane forests, montane cloud forests, tropical rain forests, tropical semi-deciduous forests, tropical dry forests, and deserts) and four aquatic (coral reefs, mangrove forests, kelp forests and saline lakes) ecosystems. We used semiquantitative statistical methods to assess (1) the most important agents of disturbance affecting the ecosystems, (2) the vulnerability of each ecosystem to anthropogenic and natural disturbance, and (3) the differences in ecosystem disturbance regimes and their resilience. Our analysis indicates a significant variation in ecological responses, recovery capacity, and resilience among ecosystems. The constant and widespread presence of human impacts on both terrestrial and aquatic ecosystems is reflected either in reduced area coverage for most systems, or reduced productivity and biodiversity, particularly in the case of fragile ecosystems (e.g., rain forests, coral reefs). In all cases, the interaction between historical human impacts and episodic high intensity natural disturbance (e.g., hurricanes, fires) has triggered a reduction in species diversity and induced significant changes in habitat distribution or species dominance. The lack of monitoring programs assessing before/after effects of major disturbances in Mexico is one of the major limitations to quantifying the commonalities and differences of disturbance effects on ecosystem properties.

Mapping Transnational Crime in El Salvador: New Trends and Lessons from Colombia

Since El Salvador’s civil war formally ended in 1992 the small Central American nation has undergone profound social changes and significant reforms. However, few changes have been as important or as devastating as the nation’s emergence as a central hub in the transnational criminal “pipeline” or series of recombinant, overlapping chains of routes and actors that illicit organizations use to traffic in drugs, money weapons, human being, endangered animals and other products. The erasing of the once-clear ideological lines that drove the civil war and the ability of erstwhile enemies to join forces in criminal enterprises in the post-war period is an enduring and dangerous characteristic of El Salvador’s transnational criminal evolution. Trained, elite cadres from both sides, with few legitimate job opportunities, found their skills were marketable in the growing criminal structures. The groups moved from kidnapping and extortion to providing protection services to transnational criminal organizations to becoming integral parts of the organizations themselves. The demand for specialized military and transportation services in El Salvador have exploded as the Mexican DTOs consolidate their hold on the cocaine market and their relationships with the transportista networks, which is still in flux. The value of their services has risen dramatically also because of the fact that multiple Mexican DTOs, at war with each other in Mexico and seeking to physically control the geographic space of the lucrative pipeline routes in from Guatemala to Panama, are eager to increase their military capabilities and intelligence gathering capacities. The emergence of multiple non-state armed groups, often with significant ties to the formal political structure (state) through webs of judicial, legislative and administrative corruption, has some striking parallels to Colombia in the 1980s, where multiple types of violence ultimately challenged the sovereignty of state and left a lasting legacy of embedded corruption within the nation’s political structure. Organized crime in El Salvador is now transnational in nature and more integrated into stronger, more versatile global networks such as the Mexican DTOs. It is a hybrid of both local crime – with gangs vying for control off specific geographic space so they can extract payment for the safe passage of illicit products – and transnational groups that need to use that space to successfully move their products. These symbiotic relationships are both complex and generally transient in nature but growing more consolidated and dangerous.

Fresh Food Vending Trends and Practices

Fresh food vending represents $1.5 billion in sales each year in the United States. The implications for a better understanding of fresh food vending are significant in terms of profitability and improved market share for vending operators. Of equal importance is a better understanding of the significance of the route driver on the overall fresh food vending operation. Developing a better understanding of this area of the food service industry will help vending operators increase profits and provide better product choices to consumers

Tree Islands in Everglades Landscapes: Current Status, Historical Changes, and Hydrologic Impacts on Population Dynamics and Moisture Relations, First Annual Report

In 2005 we initiated a project designed to better understand tree island structure and function in the Everglades and the wetlands bordering it. Focus was on the raised portions at the upstream end of the islands, where tropical hardwood species adapted to well-drained conditions usually are the most prominent component of the vegetation. The study design is hierarchical, with four levels; in general, a large number of sites is to be surveyed once for a limited set of parameters, and increasingly small sets of islands are to be sampled more intensively, more frequently, and for more aspects of ecosystem function. During the first year of the 3-year study, we completed surveys of 41 Level 1 (i.e., the least intensive level) islands, and established permanent plots in two and three islands of Levels 2 and 4 intensity, respectively. Tree species richness and structural complexity was highest in Shark Slough “hammocks”, while islands in Northeast Shark Slough and Water Conservation Area 3B, which receive heavy human use, were simpler, more park-like communities. Initial monitoring of soil moisture in Level 4 hammocks indicated considerable local variation, presumably associated with antecedent rainfall and current water levels in the adjacent marsh. Tree islands throughout the study area were impacted significantly by Hurricanes Katrina and Wilma in 2005, but appear to be recovering rapidly. As the project continues to include more islands and repeated measurements, we expect to develop a better grasp of tree island dynamics across the Everglades ecosystem, especially with respect to moisture relations and water levels in the adjacent marsh. The detailed progress report which follows is also available online at http://www.fiu.edu/~serp1/projects/treeislands/tree_islands_2005_annual_report.pd

Time trends and predictors of initiation for cigarette and waterpipe smoking among Jordanian school children: Irbid, 2008-2011

Smoking prevalence among adolescents in the Middle East remains high while rates of smoking have been declining among adolescents elsewhere. The aims of this research were to (1) describe patterns of cigarette and waterpipe (WP) smoking, (2) identify determinants of WP smoking initiation, and (3) identify determinants of cigarette smoking initiation in a cohort of Jordanian school children. ^ Among this cohort of school children in Irbid, Jordan, (age ≈ 12.6 at baseline) the first aim (N=1,781) described time trends in smoking behavior, age at initiation, and changes in frequency of smoking from 2008–2011 (grades 7–10). The second aim (N=1,243) identified determinants of WP initiation among WP-naïve students; and the third aim (N=1,454) identified determinants of cigarette smoking initiation among cigarette naïve participants. Determinants of initiation were assessed with generalized mixed models. All analyses were stratified by gender. ^ Baseline prevalence of current smoking (cigarettes or WP) for boys and girls was 22.9% and 8.7% respectively. Prevalence of ever- and current- any smoking, cigarette smoking, WP smoking, and dual cigarette/WP smoking was higher in boys than girls each year (p<0.001). At all time points, prevalence of WP smoking was higher than that of cigarette smoking (p<0.001) for both boys and girls. WP initiation was documented in 39% of boys and 28% of girls. Cigarette initiation was documented in 37% of boys and 24% of girls. Determinants of WP initiation included ever-cigarette smoking, low WP refusal self-efficacy, intention to smoke, and having teachers and friends who smoke WP. Determinants of cigarette smoking initiation included ever-WP smoking, low cigarette refusal self-efficacy, intention to start smoking cigarettes, and having friends and family who smoke.^ These studies reveal intensive smoking patterns at early ages among Jordanian youth in Irbid, characterized by a predominance of WP smoking. WP may be a vehicle for tobacco dependence and subsequent cigarette uptake. The sizeable incidence of WP and cigarette initiation among students of both sexes points to a need for culturally relevant smoking prevention interventions. Gender-specific factors, refusal skills, and smoking cessation of both WP and cigarettes for youth and their parents/teachers would be important components of such initiatives. ^